UFAs lead to complications of acute pancreatitis

Pancreatitis is an inflammatory disorder of the pancreas frequently caused by gallstones or alcohol abuse. Affecting close to 275,000 people in the United States each year, it is the nation's most expensive inpatient gastrointestinal condition, with annual hospitalization costs of more than $2 billion.

Mild acute pancreatitis, which accounts for 80 percent of cases, is self-limiting and usually resolves within three to five days with supportive management. The remaining cases are severe and have a 40 to 50 percent mortality rate when associated with local and systemic complications such as severe pancreatic necrosis and multisystem organ failure.

According to Vijay P. Singh, MBBS, a specialist in pancreas disorders at Mayo Clinic in Scottsdale, Ariz., patients who are obese are more likely to develop severe acute pancreatitis and to experience poor outcomes, including respiratory and renal failure and pancreatic necrosis. He attributes this to toxic unsaturated fatty acids (UFAs) released by lipolysis of visceral adipocyte triglycerides.

"We know that people who are obese are at greater risk of adverse outcomes after trauma, severe burns and other acute inflammatory conditions, and it appears that lipotoxic products from the breakdown of excess adipose tissue are to blame," he explains.

Tracking lipotoxicity

To understand the underlying mechanisms in acute pancreatitis, Dr. Singh and colleagues at the University of Pittsburgh began by examining pancreatic tissue from 24 patients who had died of the disease. Staining patterns and in vitro studies showed that UFAs derived from excess intrapancreatic fat contributed to pancreatic necrosis in these patients.

Dr. Singh explains, "It turns out that as we become obese, visceral fat composition changes. We accumulate more unsaturated fat — several pounds of it — within adipocytes. In people — and mice — who are obese, two-thirds to three-fourths of internal fat is unsaturated whereas in lean people, it's about 50 percent unsaturated and 50 percent saturated. And saturated fats do not cause the adverse effects that unsaturated fats do."

In the next study phase, researchers devised a cell culture system that simulated the unpolarized release of acinar enzymes.

Normally, the acinar cells, which are polarized, secrete zymogen enzymes from the apical poles of the cells into the ductal lumen, away from adipose tissue. But pancreatitis causes leakage of the enzymes into the pancreas, cleaving UFAs from adipose triglycerides. The result is impaired acinar cell activity, inhibited mitochondrial function and cell death.

In a final step, researchers used orlistat to inhibit lipolysis in obese mice with pancreatitis. This prevented a rise in serum UFAs, reduced damage to the lungs and kidneys, and, more important, reduced mortality.

"The pancreas is a visceral, mysterious and intangible organ that we seldom sample, and this has caused many therapeutic roadblocks," Dr. Singh says. "We never clearly understood that modifying factors change outcomes. We treated the mechanisms related to the initiating cause because we thought that was what we needed to do. This was based on animal models in which severity was directly related to the initiating cause. However, treating mechanisms related to the cause had no bearing on outcomes. We did not treat the modifier, which is obesity. So now we are taking one step back and developing therapeutics related to this. If we can block lipases that cleave fatty acids, we can improve outcomes."

One innovative therapy, currently being studied in animal models, involves temporarily cooling the pancreas with a water-filled balloon endoscopically placed in the stomach. The aim is to stop the complex signaling cascades that occur in pancreatitis.

"Think of refrigeration," Dr. Singh says. "Keeping food cold prevents decay by slowing, if not stopping, most if not all signaling cascades. In this case, we are not cooling the whole organism, just the pancreas. A short while at a low temperature without compromising other systems would stop multiple signaling cascades in pancreatitis."

Other areas of investigation include ways to reduce lipotoxicity itself. Dr. Singh notes this is important not just for pancreatitis but also for other sudden, inflammatory illnesses worsened by fats. "Our studies suggest that UFAs generated from lipolysis contribute to inflammation, necrosis, multisystem organ failure and mortality in acute pancreatitis associated with obesity and that inhibition of lipolysis reduces these outcomes. On the other hand, UFAs administered through various routes can cause respiratory distress and renal toxicity, so we have to look at the role of diet and nutrition in acute outcomes."

He adds, "Patients on total parental nutrition receive IV lipids from soybean oil, which is 60 percent linoleic acid and linolenic acid triglyceride. If these fatty acids are released by lipolysis, they can be highly toxic. Clinical data show that patients on IV lipids have worse outcomes in acute pancreatitis. Our studies are helping target what needs to be targeted and that includes the fats we consume."

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